PROJECT SUMMARY/ABSTRACT Several groups, including ours, have independently reported that certain individuals, here termed Non- Demented individuals with Alzheimer?s Neuropathology (NDAN), remain cognitively intact despite the presence of typical Alzheimer?s Disease (AD) neuropathology ? extracellular amyloid beta (A?) aggregates and hyperphosphorylated tau-containing intracellular neurofibrillary tangles (NFTs). The main goal of our research is to unveil the yet unknown mechanisms responsible for preservation of cognitive function in NDAN in order to develop novel effective therapies to treat AD, which will be centered on inducing cognitive resistance in anyone affected by AD. Synaptic dysfunction due to the disrupting binding of toxic small A? and tau oligomers is one of the earliest impairments in AD, believed to drive initial cognitive decline and ultimately clinical manifestation of the disease. In previous work we found that synapses of NDAN subjects are resistant to the dysfunctional binding of toxic A? oligomers, a previously unappreciated phenomenon consistent with their evading clinical manifestation of AD. In order to gain a more comprehensive understanding of synaptic resistance to A? oligomers in NDAN individuals, we further performed proteomics of post-synaptic density (PSD) fractions of hippocampi of control (non-demented, age-matched), AD and NDAN and determined that the PSD of NDAN subjects has a unique protein signature, consistent with their unique ability to reject the toxic A? oligomers. Through the predictive analysis of these proteomic data, specific miRNAs were identified as potential regulators of the unique protein signature observed at NDAN PSD. In the present project, which is the next step toward achieving our main research goal, we will use ex-vivo and in-vivo models to determine whether these selected miRNAs allow synapses to acquire resistance to A? oligomer binding and toxicity. The extensive training I will receive while completing this project will advance my knowledge of neuroscience, and in particular Alzheimer?s Disease, my overall research skills and will help me become more intellectually mature. It will also allow me to learn additional experimental techniques, particularly electrophysiology, improving my skills and preparing me for the next step in the pursuing of a future career as an independent researcher.